(2S)-2-Benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl )propionic acid (hereinafter, may also be referred to as “mitiglinide”) or a salt thereof acts as an insulin releasing factor, and thus has a potent blood glucose lowering action (see Patent Document 1). In particular, mitiglinide calcium hydrate [product name: GLUFAST (registered trademark)], which is a preparation utilizing a calcium salt dihydrate of the subject compound, is highly valued as a drug for improving the postprandial blood glucose profile in Type 2 diabetes mellitus.
Although a number of methods for producing mitiglinide and salts thereof have been previously proposed (see Patent Documents 2 and 3), none of these methods provide a reaction yield and optical purity that are necessarily sufficient, and further improvement is needed in order to produce pharmaceutical grade mitiglinide and salts thereof more efficiently. Furthermore, since it is often difficult to purify the very compounds of mitiglinide and salts thereof, it is required to produce mitiglinide with high optical purity during the production steps, at a sufficient conversion rate with a good yield. As a method for producing optically active benzylsuccinic acid, there is known a production method including catalytically reducing benzylidene succinic acid using a chiral diphosphine complex of a transition metal such as ruthenium, as an asymmetric hydrogenation catalyst (see Patent Document 4). However, this method does not offer satisfactory optical purity, and in order to enhance the optical purity, it is necessary to add more purification operations after completion of the catalytic reduction.
Recently, there has been reported a method for producing mitiglinide by subjecting the carbon-carbon double bond moiety of 2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid (see Patent Document 5), to an asymmetric reduction reaction using a rhodium complex compound having (2S,4S)-N-(t-butoxycarbonyl)-4-diphenylphosphino-2-diphenylphosphinom ethylpyrrolidine (hereinafter, may also be referred to as “BPPM”) as an asymmetric ligand (see Patent Document 6). However, the inventors of the present invention performed additional tests on this method, and it was revealed that this method is unsatisfactory as an industrial production method, because the method requires a long time to complete the reaction since the reaction rate is very slow with a conventional amount of the catalyst, and because the molar ratio of the substrate and the asymmetric catalyst (hereinafter, indicated as “S/C”) that are required to make the reaction proceed is low, thus it being essential to use expensive noble metal catalysts in large quantities.
As for the asymmetric ligand in the rhodium complex compound for asymmetric reduction, there are also known compounds having dicyclohexylphosphine as the phosphine moiety at the 4-position of pyrrolidine (see Patent Documents 7 and 8), and known are not only carbamate type compounds having a t-butoxycarbonyl group or the like, as in the case of BPPM, as a substituent on the nitrogen atom of pyrrolidine, but also urea type compounds having a t-butylaminocarbonyl group or the like as the substituent (see Patent Documents 7 to 9).
Furthermore, since mitiglinide has a low melting point and is difficult to purify by recrystallization or the like, development of a method capable of producing a benzylsuccinic acid derivative having excellent optical purity, at the highest possible purity that can be provided by the production process, is desired.
Patent Document 1: JP-A No. 4-356459
Patent Document 2: JP-A No. 6-340622
Patent Document 3: JP-A No. 6-340623
Patent Document 4: JP-A No. 5-170718
Patent Document 5: JP-A No. 4-330055
Patent Document 6: JP-T No. 2002-507222
Patent Document 7: Japanese Patent No. 2544926
Patent Document 8: Japanese Patent No. 2617329
Patent Document 9: Japanese patent No. 2816555